Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells
Rania Harati1, Marc Vandamme1, Benoit Blanchet1
1Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy (R.H.), and Department of Clinical Sciences, College of Medicine (R.A.H), University of Sharjah, Sharjah, United Arab Emirates; Centre de Recherche Saint-Antoine (R.H., M.V., F.P., C.D.-M.) and Centre de Recherche des Cordeliers (C.D.-M.), Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, CARPEM, Paris, France (B.B., C.B.); UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, Université de Paris, PRES Sorbonne Paris Cité, Paris, France (B.B); Centre National de la Recherche Scientifique, Paris, France (F.P.); and Division of Surgery and Interventional Science, UCL, London, United Kingdom (R.A.H.).
Abstract:
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.
Insights
Metformin administration can reduce sorafenib's effectiveness against liver cancer (hepatocellular carcinoma). Sequential dosing, particularly metformin before sorafenib, significantly impairs tumor growth inhibition compared to combined use.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a major global cancer burden.
- Sorafenib is a standard first-line treatment for advanced HCC.
- Clinical data suggests a survival disadvantage for HCC patients treated with sorafenib and metformin concurrently.
Purpose of the Study:
- To investigate the impact of metformin on sorafenib's anti-tumor efficacy in HCC.
- To compare concomitant versus sequential administration of metformin and sorafenib.
- To explore the underlying molecular mechanisms of drug interaction.
Main Methods:
- Utilized a subcutaneous xenograft model of human HCC in mice.
- Administered metformin and sorafenib via concomitant and sequential dosing regimens.
- Performed in vitro experiments on human HCC cell lines.
- Conducted transcriptomic analysis of tumor tissues.
Main Results:
- Sequential administration of metformin prior to sorafenib significantly reduced tumor growth inhibition (15.4%) compared to concomitant administration (59.5%).
- Metformin pretreatment decreased sorafenib's effects on HCC cell viability, proliferation, and signaling in vitro.
- Transcriptomic analysis revealed distinct molecular profiles between the dosing regimens.
- Defective AMP-activated protein kinase pathway activation was observed.
Conclusions:
- The timing of metformin administration critically affects sorafenib's anti-tumor activity in HCC.
- Concurrent use of metformin with sorafenib may compromise treatment efficacy and patient survival.
- These findings warrant caution regarding the combined use of metformin and sorafenib in diabetic HCC patients.
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